Melanoma is an extremely aggressive tumor and is considered to be an extremely immunogenic tumor because compared to other cancers it usually presents a well-expressed lymphoid infiltration. The aim ...of this paper is to perform a multidisciplinary comprehensive review of the evidence available about the combination of radiotherapy and immunotherapy for melanoma. Radiation, in fact, can increase tumor antigens visibility and promote priming of T cells but can also exert immunosuppressive action on tumor microenvironment. Combining radiotherapy with immunotherapy provides an opportunity to increase immunostimulatory potential of radiation. We therefore provide the latest clinical evidence about radiobiological rationale, radiotherapy techniques, timing, and role both in advanced and systemic disease (with a special focus on ocular melanoma and brain, liver, and bone metastases) with a particular attention also in geriatric patients. The combination of immunotherapy and radiotherapy seems to be a safe therapeutic option, supported by a clear biological rationale, even though the available data confirm that radiotherapy is employed more for metastatic than for non-metastatic disease. Such a combination shows promising results in terms of survival outcomes; however, further studies, hopefully prospective, are needed to confirm such evidence.
We investigated the frequency of detection and the prognostic and predictive significance of circulating tumor cells (CTCs) in patients with recurrent/metastatic (R/M) head and neck carcinoma (HNC) ...before starting systemic therapy.
Using the CellSearch technology, CTCs were assessed prospectively in peripheral blood of 53 R/M-HNC patients. We performed spiking experiments to test the diagnostic performance of the CellSearch platform in identifying squamous carcinoma cells.
CTCs were identified in 14 (26%) and 22 (41%) patients at baseline and at any time point, respectively. In univariate analysis ≥2 CTCs had a poorer prognostic role than 0-1 CTC. In multivariate analysis, the presence of one CTC or more was associated with a poor prognosis both in terms of progression-free survival (PFS) Hazard Ratio (HR): 3.068, 95% confidence interval (CI): 1.53-6.13, p 0.002 and overall survival (OS) HR: 3.0, 95% CI: 1.48-6.0, p 0.002. A disease control after systemic therapy was obtained in 8% of CTC-positive patients as opposed to 45% in CTC-negative ones (p 0.03). The epidermal growth factor receptor (EGFR) expression was identified in 45% of CTC-positive patients.
In conclusion, CTCs are detected in one out of three patients with RM-HNC. CTC detection is a strong prognostic parameter and may be predictive of treatment efficacy. The frequency of EGFR expression in CTCs seems to be lower than that expected in the primary tumor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Oral mucositis is a complication of radiotherapy used for head-neck cancer treatment. • Rosiglitazone protects normal tissues from radiation-induced oral mucositis. • Rosiglitazone does ...not protect the tumor from therapeutic effect of irradiation. • Rosiglitazone could be proposed as radioprotective agent in head-neck cancer.
Trabectedin is used for the treatment of advanced soft tissue sarcomas (STSs). In this study, we evaluated if trabectedin could enhance the efficacy of irradiation (IR) by increasing the intrinsic ...cell radiosensitivity and modulating tumor micro-environment in fibrosarcoma (HS 93.T), leiomyosarcoma (HS5.T), liposarcoma (SW872), and rhabdomyosarcoma (RD) cell lines. A significant reduction in cell surviving fraction (SF) following trabectedin + IR compared to IR alone was observed in liposarcoma and leiomyosarcoma (enhancement ratio at 50%, ER50: 1.45 and 2.35, respectively), whereas an additive effect was shown in rhabdomyosarcoma and fibrosarcoma. Invasive cells' fraction significantly decreased following trabectedin ± IR compared to IR alone. Differences in cell cycle distribution were observed in leiomyosarcoma and rhabdomyosarcoma treated with trabectedin + IR. In all STS lines, trabectedin + IR resulted in a significantly higher number of γ-H2AX (histone H2AX) foci 30 min compared to the control, trabectedin, or IR alone. Expression of ATM, RAD50, Ang-2, VEGF, and PD-L1 was not significantly altered following trabectedin + IR. In conclusion, trabectedin radiosensitizes STS cells by affecting SF (particularly in leiomyosarcoma and liposarcoma), invasiveness, cell cycle distribution, and γ-H2AX foci formation. Conversely, no synergistic effect was observed on DNA damage repair, neoangiogenesis, and immune system.
Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have ...been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion).
Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.
Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio HR unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals 95% CI, 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52).
To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.
The landscape of systemic therapies for advanced non-melanoma skin cancers has been revolutionized by the advent of immunotherapy. Cemiplimab is the only immune checkpoint inhibitor (ICI) approved by ...the European Medicine Agency for recurrent/metastatic cutaneous squamous cell carcinoma (cSCC). Its excellent efficacy outcomes are achieved due to its good tolerability profile. The drug-related hypersensitivity reaction (HSR) is a well-known issue in oncology, but it is rarely reported in respect to immune checkpoint inhibitors. Cemiplimab is among the agents with the best infusion tolerability profiles. Clinical practice guidelines in this field are lacking.
We report on the successful management of a severe infusion reaction induced by Cemiplimab in a patient with cSCC based on a desensitization protocol, which led to adequate treatment delivery and prolonged clinical benefit. A review of the available literature on HSR rates and its management with ICIs, and on drug desensitization (DD) protocols and their efficacy, was conducted to highlight the limited knowledge on this topic and its importance.
Our experience highlights the need for a DD protocol in order to improve the treatment of HSRs, particularly when elicited by an immunotherapy agent, preventing treatment discontinuation and preserving its efficacy.
To evaluate with a randomized clinical trial the possibility of treating the index quadrant with external intensity-modulated radiotherapy (IMRT) in a selected group of patients with early-stage ...breast cancer and to analyze the acute toxicity.
From September 2005, a randomized Phase III clinical trial has been conducted to compare conventional (tangential field) fractionated whole breast treatment (Arm A) with accelerated partial breast irradiation plus intensity-modulated radiotherapy (Arm B). For intensity-modulated radiotherapy, the clinical target volume was drawn with a uniform 1-cm margin around the surgical clips in three dimensions. The ipsilateral and contralateral breast, ipsilateral and contralateral lung, heart, and spinal cord were contoured as organs at risk. All the regions of interest were contoured according to the International Commission on Radiation Units and Measurements reports 50 and 62 recommendations.
In September 2008, 259 patients were randomized and treated. The mean clinical target volume in Arm B was 44 cm(3) and the mean planning target volume was 123 cm(3). The mean value of the ratio between the planning target volume and the ipsilateral breast volume was 21%. The rate of Grade 1 and Grade 2 acute skin toxicity was 22% and 19% in Arm A (Radiation Therapy Oncology Group scale), respectively. The tolerance in Arm B was excellent with only 5% Grade 1 and 0.8% Grade 2 acute skin toxicity. The planning constraints were fully satisfied in most patients. In a very few cases, this was not possible because of very unfavorable anatomy. Quality assurance procedures were performed according to our internal quality assurance protocol, with excellent results.
In the present preliminary analysis, we have demonstrated that accelerated partial breast irradiation is feasible, with very low acute toxicity.
Background
Oral mucositis is a side effect of treatment regimens containing 5‐fluorouracil (5‐FU). The purpose of this study was to present our evaluation to see if rosiglitazone (RGZ) protected ...normal tissues from chemotherapy‐induced oral mucositis.
Methods
C57BL/6J mice were treated with 5‐FU for 5 days, with or without RGZ. Mice were euthanized after 5, 8, 11, or 15 days, and mucosal segments were collected.
Results
The RGZ did not affect the 5‐FU‐induced decrease in mouse body weight. The 5‐FU caused loss of epithelial architecture, collagen fiber impairment, and inflammatory infiltration. The RGZ reduced leukocyte infiltration, preserved tissue structure, and dampened the 5‐FU‐induced expression of p53 and matrix metalloproteinase (Mmp)‐2 after 5 days, and of Mmp‐2 and interleukin (Il‐1β after 15 days. The RGZ inhibited the 5‐FU‐induced increase of transforming growth factor‐beta (TGF‐β) and nuclear factor‐kappa B (NF‐κB) proteins and restored collagen protein levels.
Conclusion
The RGZ had a protective effect on oral mucosa damaged by chemotherapy. These data encourage the further study of RGZ for the prevention of 5‐FU‐induced mucositis in patients with cancer.
•Head and neck squamous cell carcinoma is an immune suppressive malignancy.•Conventional intensification strategies didn’t provide any incremental benefit.•Inhibiting the PD-1/PD-L1 checkpoint may ...synergize with cetuximab and radiotherapy.
Head and neck squamous cell carcinoma (HNSCC) has been increasingly recognized as an immune suppressive malignancy. The efficacy of immune checkpoint inhibitors (ICI’s) in the context of recurrent/metastatic (R/M) setting anticipates the possible integration of immunotherapy into the therapeutic armamentarium of locally advanced disease. Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising data in R/M HNSCC. The aim of our study is to test the antitumor activity of a combined regimen incorporating an immune checkpoint inhibitor into a conventional bio-radiation strategy for the cure of unfavorable locally advanced HNSCC.
In this open label, multi-center, single-arm, phase I/II study, enrolled patients will receive Radiotherapy (RT) (69.9 Gy/2.12 Gy in 33 fractions) with concurrent Cetuximab (CTX) (400 mg/m2 1 week before RT start followed by 250 mg/m2 weekly) and DUR (fixed dose of 1500 mg every 4 weeks starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk (≥N2a or ≥T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx (≥T2, ≥N2b, ≥10 pack/years) will be eligible.
Conventional intensification strategies failed to provide any benefit for the cure of locally advanced HNSCC. For the still prevalent HPV-negative population and the high risk-HPV positive disease, there is an unmet need for alternative treatment paradigms. Potentially, the inhibition of the PD-1/PD-L1 checkpoint may synergize with both CTX and RT through immunologic interplay, ultimately aiming to reverse the HNSCC-induced immune suppression. The DUCRO study will seek to demonstrate if such a strategy may be safe and active.
NCT number: NCT03051906
Eudract number: 2016-004668-20
To determine dose constraints that correlate with alopecia in patients treated with photon-based Volumetric Modulated Arc Therapy (VMAT) for primary brain tumors.
During the treatment planning ...process, the scalp was drawn as a region of interest. Dose received by 0.1 cc (D
), mean dose (D
), absolute volumes receiving different doses (V
, V
, V
, V
, V
, V
, and V
) were registered for the scalp. Alopecia was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Receiver operating characteristics (ROC) curve analysis was used to identify parameters associated with hair-loss.
One-hundred and one patients were included in this observational study. At the end of radiotherapy (RT), 5 patients did not develop alopecia (D
scalp 3.1 Gy). The scalp of the patients with G1 (
= 11) and G2 (
= 85) alopecia received D
of 10.6 Gy and 11.8 Gy, respectively. At ROC analysis, V
≥ 5.2 cc were the strongest predictors of acute alopecia risk. Chronic hair-loss assessment was available for 74 patients: median time to recovery from G2 alopecia was 5, 9 months. The actuarial rate of hair regrowth was 98.1% at 18 months after the end of RT. At ROC analysis, V
≥2.2 cc were the strongest predictors of chronic G2-alopecia risk. V
, V
, and D
were shown to be independent variables according to correlation coefficient r.
V
and V
were the strongest predictors for acute and chronic G2 hair-loss, respectively. The low-dose bath typical of VMAT corresponds to large areas of acute but transient alopecia. However, the steep dose gradient of VMAT allows to reduce the areas of the scalp that receive higher doses, minimizing the risk of permanent alopecia. The application of our dosimetric findings for the scalp may help in reducing the alopecia risk and also in estimating the probability of hair-loss during patient counseling before starting radiotherapy.
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