Immunotherapy and Radiotherapy as an Antitumoral Long-Range Weapon—A Partnership with Unsolved Challenges: Dose,Fractionation, Volumes,Therapeutic Sequence

Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering—via synergistic effects—the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a “hot” immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death).     

新肿瘤治疗模式:化疗联合免疫治疗

化疗不仅限于细胞毒性作用,也能激活抗肿瘤免疫反应。化疗通过释放肿瘤细胞抗原、调节T细胞功能、重构免疫微环境和减少免疫抑制细胞等机制激活免疫反应,临床研究支持化疗联合免疫治疗可以提高抗肿瘤效果。系统化疗和免疫治疗的联合可能成为二代肿瘤化疗的标准模式。本文对化疗联合免疫治疗的作用机制、临床研究和模式作一综述。     

鼻咽癌非常规分割放射治疗

随着现代放射生物学的进展,肿瘤放射治疗学家对肿瘤细胞增殖特性及单次分割剂量对正常晚期组织放射损伤的影响逐渐有了深刻的理解．并通过改变分割方式来提高肿瘤治疗疗效及减小晚期正常组织损伤。全文就非常规分割放疗中常用的单纯超分割、缩短疗程的加速分割和加速超分割及其与化疗的综合治疗在鼻咽癌治疗中的应用情况作一综述。     

Radiotherapy in combination with systemic therapies for brain metastases: current status and progress

Brain metastases (BMs) are the most common cause of intracranial neoplasms in adults with poor prognosis. Most BMs originate from lung cancer, breast cancer, or melanoma. Radiotherapy (RT), including whole brain radiotherapy (WBRT) and stereotactic radiation surgery (SRS), has been widely explored and is considered a mainstay anticancer treatment for BMs. Over the past decade, the advent of novel systemic therapies has revolutionized the treatment of BMs. In this context, there is a strong rationale for using a combination of treatments based on RT, with the aim of achieving both local disease control and extracranial disease control. This review focuses on describing the latest progress in RT as well as the synergistic effects of the optimal combinations of RT and systemic treatment modalities for BMs, to provide perspectives on current treatments.     

Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model

We previously demonstrated that blockade of immune suppressive CTLA-4 resulted in tumor growth delay when combined with chemotherapy in murine mesothelioma. Tumor-infiltrating T cells (TIT) after local radiotherapy (LRT) play critical roles in abscopal effect against cancer. We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal. The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect. Growth delay of the second tumors was achieved when the primary tumor was radiated. LRT resulted in more T cell infiltration into both tumors, including Treg and cytotoxic T cells. Interestingly, the proportion of Treg over effector T cells in both tumors was reversed after CTLA-4 blockade, while CD8 T cells were further activated. The expression of the immune-related genes was upregulated and cytokine production was significantly increased. LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors. The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.     

局部晚期非小细胞肺癌的非常规分割放射治疗

近几年随着放射生物学的发展,非常规分割放射治疗进步很大.全文综述非常规分割放射治疗局部晚期非小细胞肺癌的进展.     

鼻咽癌治疗中的放疗联合免疫治疗

鼻咽癌的临床治疗中,放疗和免疫治疗都取得了肯定的疗效。但只有部分患者受益于免疫治疗,这与T细胞的免疫应答等有关。放疗在鼻咽癌的治疗中有着极高的肿瘤控制率,但放疗的毒性作用以及对患者生存质量的影响不容忽视。放疗具有免疫调节作用,使得放疗和免疫治疗的联合为鼻咽癌的治疗提出一个新方向。全文就放疗和免疫治疗在鼻咽癌治疗中的作用机制,以及两者联合应用的现况作一综述。     

化疗加后程加速超分割放射治疗食管癌的疗效分析

目的 :评价化疗加后程加速超分割放射治疗食管癌的疗效。方法 :118例食管癌患者 ,随机分为 2组 (化放组与单放组 ) ,每组 5 9例。放疗采用 6MVX线外照射 ,前 2 / 3疗程常规放射治疗 2Gy/次 ,共 4 0Gy ;后 1/ 3疗程改用加速超分割放射治疗 (2次 /天 ,1 35～ 1 4Gy/次 ) ,全疗程总剂量共 6 7～ 6 8Gy ,4 0分次 ,4 0～ 4 2天完成 ;化疗采用FP方案 (5 氟脲嘧啶和顺铂 )。结果 :化放组与单放组的 1、2年生存率分别为 86 4 %、6 9 5 %和 72 9%、5 0 8% (χ2 =3 95 ,4 2 8,P <0 0 5 ) ,其中 3、4年生存率分别为 4 9 2 %、4 2 4 %和 4 0 7%、33 9% (χ2 =0 86 ,0 89,P >0 0 5 )。结论 :化疗加后程加速超分割放射治疗食管癌能提高患者的近期生存率 ,并未增加毒性反应。     

Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination

Immunotherapy has revolutionized the management of cancers. At the end of 2018, 1,716 clinical trials assessed regimen that combine program death-1 (PD-1)/program death ligand-1 (PD-L1) blockers with other cancer therapies (tyrosine kinase inhibitor, chemotherapy and radiotherapy). There is a contrast between these clinical dynamics and the difficulty of identifying biomarkers to better select patients that could benefit from immunotherapy. In this context, different tumor classifications have been proposed to try to better stratify patients. They rely on the characteristics of the tumor microenvironment and led first to divide them into hot and cold tumors. In this review, we aim to demonstrate the limitations of this classification focusing on the differential significance of subpopulations of intratumor CD8 + T cells. We also underline novel mechanisms of resistance to anti-PD-1/PD-L1 blockade, focusing on myeloid cells, hypoxia and tumor immunoediting under treatment. Understanding the mechanisms of resistance to immune-checkpoint inhibitor is indeed a powerful research driver that allows further identification of novel biomarkers, drug development and bring a rational to innovative therapeutic combinations.     

15例脊髓空洞症放射治疗疗效分析

目的：探讨放射治疗对脊髓空洞症的治疗作用。方法：回顾性分析1993年3月至2001年月该院共收治的15例脊髓空洞症患者的疗效，采用钴60或6MV X线或电子束照射，剂量21.6Gy，分次量为1.2Gy／次，每周5次。结果：完全恢复（CR）2例，好转（PR）8例，有效率66．7％，稳定（SD）3例，进展（PD）2例，全组均无明显放疗反应。结论：放射治疗是脊髓空洞症的一种重要的治疗方法，合并Chiari畸形及病程较长者疗效较差。     

International Variations in Radiotherapy Fractionation for Bone Metastases: Geographic Borders Define Practice Patterns?

Although it may be argued that single fraction (SF) radiotherapy (RT) should be regarded as the standard palliative treatment for pain due to uncomplicated bone metastases, its widespread clinical use is still underexploited. In this chapter, the authors discuss a number of surveys investigating doctors and patients' preferences for palliative RT schedules, discuss the possible reasons for this phenomenon, and suggest potential strategies to increase the use of SF.     

Chimeric antigen receptor transduced T cells: Tuning up for the next generation

Chimeric antigen receptor (CAR) T cell therapy has recently achieved impressive clinical outcome in patients with CD19‐positive hematologic malignancies. Extrapolation of CAR T cell treatment to solid tumors, however, has not yet yielded similar results. This might be due to intrinsic causes, e.g. insufficient CAR T cell activation or CAR toxicity as well as extrinsic factors displaying an unfavorable tumor environment for CAR T cells by raising physical and chemical barriers. In this review, we discuss the advantages as well as major obstacles of CAR T cell therapy, particularly in the context of solid tumors, and focus on efforts and novel strategies in CAR T cell development.     

局限期小细胞肺癌放化疗综合治疗

[目的]研究常规放疗及加速超分割放疗联合化疗治疗局限期小细胞肺癌的近期疗效及生存期.[方法]1998年2月至2000年5月间,局限期小细胞肺癌共72例随机分为2组,常规放疗组34例和加速超分割放疗组38例.两组接受EP方案化疗2个疗程后开始放疗.常规放疗组2Gy/次,每天1次,每周5次,总量(56～60)Gv/(5.6～6)w.加速超分割组放疗1.4Gy/次,每日2次,2次间隔≥6小时,每周5日,总量56Gy/4w.放射野包括原发灶,同侧肺门、纵隔淋巴引流区.2组病人在完成放疗后继续EP方案化疗4个疗程.[结果]全组总有效率77.8%,中位生存期18个月,常规放疗组和加速超分割放疗组两组近期疗效分别为70.6%和84.2%(P＞0.05),两组1、2、3年生存率分别为76.5%、23.3%、10.9%和80.0%、32.6%、11.7%(P＞0.05).[结论]加速超分割放疗组的近期疗效及长期生存率等同于常规分割放疗组.     

立体定向放射治疗脊柱转移瘤疗效分析

目的观察立体定向放射治疗脊柱转移瘤的疗效与不良反应。方法应用全身伽玛刀治疗脊柱转移瘤24例，肿瘤组织照射剂量38．2～46．8Gy，10～13分次，13～17天完成。结果放疗后疼痛完全缓解（CR）7例，部分缓解（PR）12例，轻微疗效（MR）2例，止痛有效率90．5％。骨转移灶完全消失3例，明显缩小13例，治疗后生活质量评分较治疗前明显改善，消化道反应和骨髓抑制等不良反应轻微。结论立体定向放射治疗脊柱转移瘤止痛效果迅速持久，能明显改善患者的生活质量，控制肿瘤效果满意，值得推广。     

立体定向放射治疗脊柱转移瘤疗效分析

目的观察立体定向放射治疗脊柱转移瘤的疗效与不良反应。方法应用全身伽玛刀治疗脊柱转移瘤24例,肿瘤组织照射剂量38.2~46.8 Gy,10~13分次,13~17天完成。结果放疗后疼痛完全缓解(CR)7例,部分缓解(PR)12例,轻微疗效(MR)2例,止痛有效率90.5%。骨转移灶完全消失3例,明显缩小13例,治疗后生活质量评分较治疗前明显改善,消化道反应和骨髓抑制等不良反应轻微。结论立体定向放射治疗脊柱转移瘤止痛效果迅速持久,能明显改善患者的生活质量,控制肿瘤效果满意,值得推广。     

The feasibility of high-dose multiple daily fractionation and its combination with anoxic cell sensitizers in the treatment of head and neck cancer a pilot study of the Radiotherapy Group of the EORTC (European Organisation for Research on Treatment of Cancer)

From 1978 to the end of 1980, 179 patients with advanced head and neck tumors were accrued in a multicenter pilot study of the EORTC Radiotherapy Group, investigating the feasibility of high dose multiple daily fractionation (MDF) and its combination with misonidazole. The irradiation scheme consisted of three daily fractions of 1.6 Gy (four hour intervals) to a total dose of 48 Gy in two weeks, followed 3 to 4 weeks later by a boost to a total of about 70 Gy in 6 to 7 weeks. Misonidazole was given in daily doses of 1 g/m² (total 13 or 14 g/m²) to 53 patients, thus sensitizing every radiation session. All patients had large head and neck tumors, with a poor prognosis. Acute reactions were well tolerated. Skin reactions were very moderate; mucosal reactions started at day 10 to 12. All patients had a confluent mucositis that lasted for one to two weeks. When the whole oral cavity was irradiated, reactions lasted somewhat longer. The boost caused no significant symptoms. The radiosensitizer did not modify the reaction pattern. Tumor regression was very impressive, so that palliation was obtained quickly. Nine patients died from treatment related causes. It is difficult to assess local control at this time, but at the time of analysis (August 1981), the actuarial control rate was 48% at 20 months, with misonidazole 57%. This difference, however, is not statistically significant. Survival of the total group is 31% at 20 months. In these patients with a heavy tumor burden the early results were considered a success by all participants. For patients with sufficient follow-up, late reactions can be evaluated. Some edema and fibrosis is seen, but did not exceed a degree which could be expected with single daily fractionation to the same dose. This study demonstrates the possibility of giving highly concentrated treatments to total doses equal to those used in conventional fractionation. For assessment of a possible benefit in local control and ultimate survival, a randomized study is necessary. Such a study is now underway in the EORTC Radiotherapy Group, comparing single daily radiotherapy with multiple daily fractionation with or without misonidazole.     

Changes in the Management of Patients having Radical Radiotherapy for Lung Cancer during the First Wave of the COVID-19 Pandemic in the UK

AimsIn response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I–III lung cancer from April to October 2020.Materials and methodsLung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I–III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression.ResultsIn total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease.ConclusionsThe COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes.     

Reduced Fractionation in Lung Cancer Patients Treated with Curative-intent Radiotherapy during the COVID-19 Pandemic

Patients treated with curative-intent lung radiotherapy are in the group at highest risk of severe complications and death from COVID-19. There is therefore an urgent need to reduce the risks associated with multiple hospital visits and their anti-cancer treatment. One recommendation is to consider alternative dose-fractionation schedules or radiotherapy techniques. This would also increase radiotherapy service capacity for operable patients with stage I-III lung cancer, who might be unable to have surgery during the pandemic.Here we identify reduced-fractionation for curative-intent radiotherapy regimes in lung cancer, from a literature search carried out between 20/03/2020 and 30/03/2020 as well as published and unpublished audits of hypofractionated regimes from UK centres. Evidence, practical considerations and limitations are discussed for early-stage NSCLC, stage III NSCLC, early-stage and locally advanced SCLC. We recommend discussion of this guidance document with other specialist lung MDT members to disseminate the potential changes to radiotherapy practices that could be made to reduce pressure on other departments such as thoracic surgery. It is also a crucial part of the consent process to ensure that the risks and benefits of undergoing cancer treatment during the COVID-19 pandemic and the uncertainties surrounding toxicity from reduced fractionation have been adequately discussed with patients. Furthermore, centres should document all deviations from standard protocols, and we urge all colleagues, where possible, to join national/international data collection initiatives (such as COVID-RT Lung) aimed at recording the impact of the COVID-19 pandemic on lung cancer treatment and outcomes.     

溃疡型食管癌单纯放疗与综合治疗的临床观察

目的　了解溃疡型食管癌单纯放疗和综合治疗的区别。方法　对本院 1994.1～ 1998.12资料完整的 32例溃疡型食管癌 (单纯放疗组 18例 ,综合治疗组 14例 )进行回顾性分析。结果　两组的近期疗效 (CR PR)分别为 88.9%和 85 .7% ,P>0 .0 5。综合治疗组的消化道反应和白细胞减少多于且重于单纯放疗组 ,P<0 .0 5 ;平均治疗时间为 78天 ,长于单纯放疗组 (6 5天 ) ,P<0 .0 5。结论　单纯放疗组较综合治疗组有治疗反应轻 ,患者易于耐受 ,治疗时间短 ,经济负担轻等优点