To present a novel method for meta-analysis of the fractionation sensitivity of tumors as applied to prostate cancer in the presence of an overall time factor.
A systematic search for radiation ...dose-fractionation trials in prostate cancer was performed using PubMed and by manual search. Published trials comparing standard fractionated external beam radiation therapy with alternative fractionation were eligible. For each trial the α/β ratio and its 95% confidence interval (CI) were extracted, and the data were synthesized with each study weighted by the inverse variance. An overall time factor was included in the analysis, and its influence on α/β was investigated.
Five studies involving 1965 patients were included in the meta-analysis of α/β. The synthesized α/β assuming no effect of overall treatment time was -0.07 Gy (95% CI -0.73-0.59), which was increased to 0.47 Gy (95% CI -0.55-1.50) if a single highly weighted study was excluded. In a separate analysis, 2 studies based on 10,808 patients in total allowed extraction of a synthesized estimate of a time factor of 0.31 Gy/d (95% CI 0.20-0.42). The time factor increased the α/β estimate to 0.58 Gy (95% CI -0.53-1.69)/1.93 Gy (95% CI -0.27-4.14) with/without the heavily weighted study. An analysis of the uncertainty of the α/β estimate showed a loss of information when the hypofractionated arm was underdosed compared with the normo-fractionated arm.
The current external beam fractionation studies are consistent with a very low α/β ratio for prostate cancer, although the CIs include α/β ratios up to 4.14 Gy in the presence of a time factor. Details of the dose fractionation in the 2 trial arms have critical influence on the information that can be extracted from a study. Studies with unfortunate designs will supply little or no information about α/β regardless of the number of subjects enrolled.
More than a decade of randomized controlled trials in prostate cancer has established a positive radiation dose response at moderate doses and a consistently low α/β ratio in the linear quadratic ...model for moderate hypofractionation. The recently published large randomized trial of ultrahypofractionated prostate cancer radiation therapy adds substantially to our current knowledge of dose response and fractionation sensitivity.
Randomized trials of dose escalation and hypofractionation of radiation therapy were meta-analyzed to yield the overall best estimate of the α/β ratio. Additionally, a putative saturation of dose effect previously reported at approximately 80 Gy EQD2 was investigated by mapping the relative effectiveness assessed at 5 years onto a single reference dose-response curve.
Meta-analysis of 14 randomized trials including 13,384 patients yielded a best estimate of α/β = 1.6 Gy (95% confidence interval, 1.3-2.0 Gy) but with highly significant heterogeneity (I
= 70%, P = .0005). Further analysis indicated an association between increasing dose per fraction in the experimental arm and increasing α/β ratio (slope, 0.6 Gy increase in α/β per Gy increase in fraction size; P = .017). This deviation from the linear quadratic model could, however, also be explained by biochemical control maxing out at doses above approximately 80 Gy.
Biochemical control data from randomized controlled trials of dose-per-fraction escalation in prostate cancer radiation therapy are inconsistent with the presence of a constant fractionation sensitivity in the linear-quadratic model and/or a monotonic dose response for biochemical control beyond 80 Gy equivalent dose. These observations have a potential effect on the optimal doses in future trials and the interpretation of ongoing trials of ultrahypofractionation.
Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the ...relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT.
A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D50,i, and the normalized dose-response gradient, γ50,i.
A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D50,TRG1=92.0 Gy (95% confidence interval CI 79.3-144.9 Gy), γ50,TRG1=0.982 (CI 0.533-1.429), and for major response (TRG1-2) D50,TRG1&2=72.1 Gy (CI 65.3-94.0 Gy), γ50,TRG1&2=0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships.
This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.
Abstract
Introduction. The risk of developing side effects after radiotherapy is not only dependent on radiation dose, but may also be affected by patient-related risk factors. Here we perform a ...literature-based meta-analysis to estimate the effect of various clinical risk factors on the incidence of symptomatic radiation pneumonitis (RP). Material and methods. A systematic review of English language articles in the Pubmed, Embase and Cochrane controlled trials registers. Studies with the mesh term "radiation pneumonitis" or the search term "radiation pneumonitis" were included. Additional studies were identified by manual searching of the references. Studies reporting crude incidence or odds ratios (OR) for radiation pneumonitis vs. age, disease location, smoking status, chemotherapy schedule or comorbidity were included. A systematic overview (meta-analysis) was conducted to synthesize data across multiple studies. Results. Significant risk factors for RP were: older age (OR = 1.7, p < 0.0001); disease located in mid-lower lung (OR = 1.9, p = 0.002); presence of comorbidity (OR = 2.3, p = 0.007). Ongoing smoking was found to protect against RP (OR = 0.6, p = 0.008). History of smoking tended to protect against RP (OR = 0.7, p = 0.06). Sequential (rather than concomitant) chemotherapy scheduling (OR = 1.6, p = 0.01) increased RP risk, but treatment intensity and patients selection are likely confounders. Conclusion. This systematic overview revealed several clinical risk factors for RP that have not been unambiguously identified in the literature. These risk factors should be considered when defining dose-volume constraints for radiation treatment plan optimization.
Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 ...expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.
The International Lymphoma Radiation Oncology Group (ILROG) guidelines for using radiation therapy (RT) in hematological malignancies are widely used in many countries. The emergency situation ...created by the COVID-19 pandemic may result in limitations of treatment resources. Furthermore, in recognition of the need to also reduce the exposure of patients and staff to potential infection with COVID-19, the ILROG task force has made recommendations for alternative radiation treatment schemes. The emphasis is on maintaining clinical efficacy and safety by increasing the dose per fraction while reducing the number of daily treatments. The guidance is informed by adhering to acceptable radiobiological parameters and clinical tolerability. The options for delaying or omitting RT in some hematological categories are also discussed.
Randomized trials of altered dose/fractionation for external beam radiation therapy are meta-analyzed with the aim of establishing the dose response and fractionation sensitivity.
Studies were ...identified through PubMed through April 1, 2017. Studies of any-risk prostate cancer patients and any modification of external beam radiation therapy were included. The outcomes and comparisons collected were hazard ratios for biochemical no evidence of disease (bNED) and overall survival (OS). Trial-by-trial estimates of the steepness of the dose-response curve for bNED were performed for dose-escalation trials, followed by inverse variance weighting. The steepness was used to extract estimates of α/β, which were subsequently synthesized. Both analyses were performed assuming no effect of overall treatment time and were repeated assuming a loss of 0.31 Gy/d for a protracted treatment time. Finally, all trials were included in the analyses of the dose response for fractionation-corrected doses. This analysis was repeated for OS. Finally, the per-trial effect on OS was compared to the effect on bNED.
We identified 13 randomized trials involving 10,184 patients. The dose response for bNED from dose-escalation trials was γ
= 0.62 (95% confidence interval CI 0.37-0.87) and γ
= 0.87 (95% CI 0.53-1.21) without and with the overall treatment time effect, respectively. The corresponding estimates of α/β from 8 fractionation trials (7946 patients) were 1.2 Gy (95% CI 0.8-1.7) and 2.7 Gy (95% CI 1.6-3.8). The heterogeneity in the data can be explained by the shallower dose response for bNED in trials with effective doses in the experimental arm >80 Gy equivalent dose in 2-Gy fractions (EQD2) (P = .04). No indication was found of a dose response for OS or a correlation with improvement in bNED.
The reported data of moderate hypofractionation are consistent with a low α/β value with narrow CIs. Dose-escalation trials have demonstrated a dose response for bNED. Escalating doses to >80 Gy EQD2 might not improve bNED. A correlation between benefit in bNED and OS was not found.
Radiation dose-volume effects in the lung Marks, Lawrence B; Bentzen, Soren M; Deasy, Joseph O ...
International journal of radiation oncology, biology, physics,
03/2010, Volume:
76, Issue:
3 Suppl
Journal Article
Peer reviewed
Open access
The three-dimensional dose, volume, and outcome data for lung are reviewed in detail. The rate of symptomatic pneumonitis is related to many dosimetric parameters, and there are no evident threshold ..."tolerance dose-volume" levels. There are strong volume and fractionation effects.
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