...in the same study, SF2 in five of 12 cell lines was predicted correctly, rising to five of nine when leukaemia cell lines were excluded.1 We have since shown that RSI predicted response to ...pre-operative chemoradiation in rectal and oesophageal cancer and locoregional recurrence survival in head and neck cancer. ...in many cases, the most important determinant of local control is surgery; therefore, a tumour's radio-resistance often has no role in its local recurrence risk. ...local control has traditionally been used as the endpoint for radiotherapy optimisation; this empirical optimisation might have abrogated intrinsic radiosensitivity differences between tumours as reflected in local control (ie, if sufficient radiation is delivered accurately, then radiosensitivity differences are less important). References 1 S Eschrich, H Zhang, H Zhao, Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform, Int J Radiat Oncol Biol Phys, Vol. 75, 2009, 497-505 2 SA Eschrich, J...
...we showed that GARD is an independent predictor of clinical outcome in five patient cohorts. ...we used GARD to predict the impact of dose escalation (50 vs 66 Gy) on distant metastasis-free ...survival in breast cancer.
To highlight the current evidence and the limitations in data to support a personalized approach in breast oncology radiation therapy management and define steps needed for clinical implementation.
A ...critical review of the current literature on the use of genomics in breast radiation therapy was undertaken by a group of breast radiation oncologists to discuss current data, future directions, and challenges.
A summary of the existing data, ongoing clinical trials, and future directions is provided. The authors note many groups have developed radiation-specific genomic assays, which demonstrate promise in prediction of local control and benefit from radiation therapy; however, prospective validation of their utility is needed. Limitations continue to exist in our understanding of tumor biology and how it can be integrated into clinical practice.
Given the relative ubiquity of breast radiation therapy, the variety of dose and fractionation approaches, and the current data to support a personalized approach, it is our belief that the delivery of breast radiation therapy is uniquely poised for a genomically personalized radiation therapy approach. Prospective clinical trials implementing genomic signatures are needed at this time to advance the field.
To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and ...benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa.
Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189).
Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders.
Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.
Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We ...hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose.
TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy.
In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1–7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1–29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy.
GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.
Bladder preservation with trimodal therapy (TMT; maximal tumor resection followed by chemoradiation) is an effective paradigm for select patients with muscle invasive bladder cancer. We report our ...institutional experience of a TMT protocol using nonadaptive magnetic resonance imaging–guided radiation therapy (MRgRT) for partial bladder boost (PBB).
A retrospective analysis was performed on consecutive patients with nonmetastatic muscle invasive bladder cancer who were treated with TMT using MRgRT between 2019 and 2022. Patients underwent intensity modulated RT-based nonadaptive MRgRT PBB contoured on True fast imaging with steady state precession (FISP) images (full bladder) followed sequentially by computed tomography–based RT to the whole empty bladder and pelvic lymph nodes with concurrent chemotherapy. MRgRT treatment time, table shifts, and dosimetric parameters of target coverage and normal tissue exposure were described. Prospectively assessed acute and late genitourinary and gastrointestinal (GI) toxicity were reported. Two-year local control was assessed with Kaplan-Meier methods.
Seventeen patients were identified for analysis. PBB planning target volume margins were ≤8 mm in 94% (n = 16) of cases. Dosimetric target coverage parameters were favorable and all normal tissue dose constraints were met. For MRgRT PBB fractions, median table shifts were 0.4 cm (range, 0-3.15), 0.45 cm (0-2.65), and 0.75 cm (0-4.8) in the X, Y, and Z planes, respectively. Median treatment time for MRgRT PBB fractions was 9 minutes (range, 6.9-17.4). We identified 32 out of 100 total MRgRT fractions that may have benefitted from online adaptation based on changes in organ position relative to planning target volume, predominantly because of small bowel (13/32, 41%) or rectum (8/32, 25%). Two patients discontinued RT prematurely. The incidence of highest-grade acute genitourinary toxicity was 1 to 2 (69%) and 3 (6%), whereas the incidence of acute GI toxicity was 1 to 2 (81%) and 3 (6%). There were no late grade 3 events; 17.6% had late grade 2 cystitis and none had late GI toxicity. With median follow-up of 18.2 months (95% CI, 12.4-22.5), the local control rate was 92%, and no patient has required salvage cystectomy.
Nonadaptive MRgRT PBB is feasible with favorable dosimetry and low resource utilization. Larger studies are needed to evaluate for potential benefits in toxicity and local control associated with this approach in comparison to standard treatment techniques.
Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of ...sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT.
A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status.
Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%;
=.036) and multivariate analysis (hazard ratioHR, 0.15; 95% CI, 0.05-0.43;
<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%;
=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%;
<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14).
Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.
Genomic-based risk stratification to personalize radiation dose in rectal cancer.
We modeled genomic-based radiation dose response using the previously validated radiosensitivity index (RSI) and the ...clinically actionable genomic-adjusted radiation dose.
RSI of rectal cancer ranged from 0.19 to 0.81 in a bimodal distribution. A pathologic complete response rate of 21% was achieved in tumors with an RSI <0.31 at a minimal genomic-adjusted radiation dose of 29.76 when modeling RxRSI to the commonly prescribed physical dose of 50 Gy. RxRSI-based dose escalation to 55 Gy in tumors with an RSI of 0.31–0.34 could increase pathologic complete response by 10%.
This study provides a theoretical platform for development of an RxRSI-based prospective trial in rectal cancer.
Long-term data establishes the efficacy of radiotherapy in the adjuvant management of breast cancer. New dose and fractionation schemas have evolved and are available, each with unique risks and ...rewards. Current efforts are ongoing to tailor radiotherapy to the unique biology of breast cancer. In this review, we discuss our efforts to personalize radiotherapy dosing using genomic data and the implications for future clinical trials. We also explore immune mechanisms that may contribute to a tumor’s unique radiation sensitivity or resistance.
PDF
